Process for the preparation of hydroxy substituted gamma butyrolactones

ABSTRACT

Preparation of 4-hydroxy substituted butyrolactones is described. A process for the preparation of 3-hydroxybutyrolactone, 1.2.4-trihydroxybutane and 3,4-dihydroxy acid methyl ester from malic acid is particularly described. The preparation of 4-hydroxymethyl-4-hydroxybutyric acid -1-methyl ester and 4-hydroxymethyl butyrolactone is particularly described. The compounds are intermediates to various pharmaceutical and agricultural products.

BACKGROUND OF THE INVENTION

(1) Summary of the Invention

The present invention relates to the preparation of hydroxy substitutedgamma butyrolactones. In particular, the present invention relates to aprocess for the preparation of isomers, in the (R) or (S) form. Further,the present invention relates to the preparation of 3hydroxybutyrolactone and derivatives thereof such as1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid-1-methyl ester frommalic acid. Further still, the present invention relates particularly tothe preparation of 4-hydroxy methyl butyrolactone from 4-hydroxybutanedicarboxylic acid dimethyl ester. The compounds as the isomers areparticularly useful as intermediates for pharmaceuticals, agrochemicalsfavors and fragrances.

(2) Description of Related Art

U.S. Pat. Nos. 4,994.597 and 5,087,751 to Inone et al describederivatives of 3,4-dihydroxybutyric acid. The pro ass for preparing theacid is different from the present invention involving a reaction ofmetal cyanide and a 3,4-dihydroxy butyl chloride and then hydrolyzing.The acid is an intermediate to 3-hydroxybutyrolactone.

(S)-3-Hydroxybutyrolactone is a key 4-carbon intermediate for thepreparation of various drug intermediates including cholesterol loweringdrugs. (S)-carnitine, and HIV protease inhibitor drugs, broad spectrumantibiotics.

(R)-3-Hydroxybutyrolactone or (R)-3,4-dihydroxybutyric acid gammalactose is a key 4-carbon intermediate for the preparation of variousdrug intermediates. It can also be converted to 1-carnitine, a naturallyoccurring vitamin and ingredient used in several applications includingtreatment of various nervous system and metabolic disorders, as anadditive in health foods and as a supplement in tonics. The world widemarket for carnitine is estimated to be in the hundreds of metric tons.It is currently made by fermentation and by resolution of the d and 1forms. There is no direct chemical route of any commercial value.

(S)-3-hydroxybutyrolactone can be prepared by the process ofHollingsworth (U.S. Pat. No. 5,374,773). (R)-3-Hydroxybutyrolactonecannot be prepared by the process since this would require the use of astarting material with a 4-linked L-hexane. No such material is known.

1-Malic acid (1-hydroxybutanedioic acid) is a 4-carbon dicarboxylic acidthat la obtained in quantity, from apple juice and wine among otherfruit juices. R can also be obtained by the hydraulics of fumaric acidand by the fermentation of sugars by some yeasts either as the free acidor as the polyester (polymalic acid). It is relatively inexpensive inisomeric forms.

There are rationally two major commercial routes to(S)-3-hydroxybutyrolactone involving enzymatic resolution. (1) One routeto (S)-3-hydroxybutyrolactone involves the reduction of the dimethylester of malic acid to (S)-1,2,4-butanetriol, the preparation of adioxolane intermediate to protect the 1 and 2 hydroxyl groups followedby oxidation of the 4-hydroxyl group to an aldehyde and then to an acid.The acid is then deprotected and the dihydroxy compound cyclized to(S)-3-hydroxybutyrolactone. This is shown by the following reaction(Scheme (I)).

This is a very involved process and has no commercial value. It iscomplicated by the fan that the dioxolane is contaminated with about 10%of the dioxane. This is difficult to remove and results in the formationof contaminating 2-hydroxybutyrolactone. The process is described inCorey, et al., (E. J. Corey, H. Niwa and I. Knolle. “Total Synthesis of(S)-12-Hydroxy-5,8,14-cis-10-transeicosatetraenoic Acid”. J. Amer. ChemSoc. 100 1942-1943(1978)).

(2) Another route involves a process for the direct reduction of malicacid to (S)-3-hydroxybutyric acid and the transformation to(S)-3-hydroxybutyrolactone. This reaction employs the dimethyl sulfidecomplex of borane and a catalytic amount of sodium borohydride as thereducing system Borane dimethyl sulfide requires specialized equipmentto handle and an oxygen free and moisture free environment. It is verytoxic and dimethyl sulfide is a very noxious gas. The reducing system isvery expensive. The process is described in Saito et al., (S. Saito, T.Hasegawa, M. Inaba, R. Nishida, T. Fujii, S. Nomizu, and T. Moriwaki.“Combination of borane-dimethyl sulfide complex with catalytic sodiumtetrahydroborate as a selective reducing agent of a-hydroxy esters,versatile chiral building block from (S)-(−)-malic acid” Chem Letts.1389-1392 (1984)).

Other references which are pertinent to the present invention are: Arthet al., Liebigs Ann. 2037-2042 (1995) who describe the production of1,2,4-butanetriol from malic acid using a borane reduction. Tandon, V.,et al., J. Org. Chem. 48:767-2769 (1983) who describe the cyclization of1.2.4-triol to tetrahydrofuran. Boger a al., 46 1208-1210 (1981) whodescribe a process for producing chiral derivatives from malic acid.Herradon, Asymmetry 2 191-194 (1991) who describes the use of aborane-dimethyl sulfide complex reduction to 1,2,4 butanetriol. This isa difficult process to practice because of problems in handling thebutane, Hanessian et al., 199 2146-2147 (1984) describe triolderivatives produced from malic acid using boranes.

The use of alkali metal borohydrides, particularly lithium borohydride,as a reducing and hydrogenerating agent are generally known in the priorart. They are described in U.S. Pat No. 2,683,721 to Schlesinger et al.These are not known for use in preparing hydroxy substituted gammabutyrolactones.

The preparation of la lactones in general is described for instance inAdvanced Organic Chemistry 1977, page 363. U.S. Pat. Nos. 3,024,250 toKlein et al., 3,868,370 to Smith, 3,997,569 to Powell, 4,105,674 to DeThomas et al., 4,155,919 to Ratatouille et al., 4,772.729 to Rao,4,940,805 to Fisher et al., 5,292,939 to Hollingsworth, 5,319,110 toHollingsworth, 5,374,773 to Hollingsworth, and 5,502,217 to Fuchikami etal. These patents describe diverse processes for the preparation oflactones. They particularly do not describe the use of malic acid as astarting material. The processes described are also relatively complex.

There is a need for an improved process for the preparation of hydroxybutyrolactones and related alcohols and acid derivatives, particularly4-hydroxy methyl butyrolactone, 3-hydroxybutyrolactone,1,2,4-butanetriol and 3,4-dihydroxy acid, methyl ester in high yield.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1, 2 and 3 are NMR spectra of (S)-3,4-dihydroxybutyric acid methylester (FIG. 1); (S)-1,2,4-butanetriol (FIG. 2) and (S)-3-hydroxy gammabutyric acid lactone (FIG. 3). The asterisk is used to designateimpurities. In each instance, the produce are as isolated withoutfurther purification. The formulas are shown in FIGS. 1A, 2A and 3A,respectively.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to a process for producing a hydroxysubstituted compound which comprises: reacting in a reaction mixture a2-hydroxy substituted alkane diacid lower alkyl diester, wherein thediacid contains 4 to 8 carbon atoms and alkyl contains 1 to 4 carbonatoms, with an alkali metal borohydride in a non-reactive solvent toproduce the hydroxy substituted compound.

The present invention relates to a process for the preparation of ahydroxy substituted gamma butyrolactone which comprises: reacting in areaction mixture a 2-hydroxy substituted alkane diacid lower alkyldiester, wherein the acid contains 4 to 5 carbon atoms and alkylcontains 1 to 4 carbon atoms, with an alkali metal borohydride in anon-reactive solvent at a temperature between about −10° and 60° C. toproduce the hydroxy substituted butyrolactone and an alcohol as aby-product.

In the process of the present invention, the preferred lithiumborohydride is generated in situ from sodium borohydride and lithiumchloride in a solvent, preferably in a mixture of tetrahydrofuran andmethanol. This reducing agent is safe to handle without specialprecaution. It is cheap and readily available. The lithium borohydrideis one-tenth the cost of the dimethyl sulfide butane complex of theprior art which is dangerous. The product of the process is isolated bya simple acidification, concentration and extraction. The yields of theprocess of the present invention are very good. Other alkali metalborohydrides are described in U.S. Pat. No. 2,683,721 to Schlesinger, etal.

The present invention particularly relates to a process for thepreparation of a compound selected from the group consisting of1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid -1-methyl ester andmixtures thereof which comprises: reacting in a reaction mixture malicacid with a molar excess (preferably more than 100%) of anhydrousmethanol in the presence of a catalytic amount of hydrogen ion and at atemperature between about 40° C. and reflux to produce hydroxy butanedioic acid dimethyl ester (2-hydroxy-succinic acid dimethyl ester); and(b) reducing the hydroxy butane dioic acid dimethyl ester with an alkalimetal, preferably lithium borohydride in the reaction mixture to producethe compound. The 3-hydroxy gamma butyrolactone can be produced byhydrolyzing the ester.

The ratio of the preferred lithium borohydride to the hydroxybutanedioic acid dimethyl ester determines the predominant product frommalic acid which is produced as is shown as follows by Scheme II for the(S) isomer and in Examples 1 to 4:

At one equivalent (eq.) the product is essentially the lactone in thepresence of added acid. With two (2) equivalents of the lithiumborohydride, the product is essentially the (S)1, 2,4-trihydroxybutane.This can be seen from the following examples. The NMR spectra am shownin FIGS. 1 to 3 with the formulas shown in FIGS. 1A, 2A and 3A.

The Process of the present invention has the advantage that the stepsare performed in the same reaction vessel. The yields are 88% a betterof the 3-hydroxybutyrolactone. The yield of the 1.2,4-trihydroxybutaneis generally greater than 96% with a molar excess of the lithiumborohydride. The preferred reaction temperature is between −10° and 60°C.

The reaction after the formation of 3.4-dihydroxybutyric acid-1-methylester as shown is Scheme II, as a result of the reduction reaction, isheated with acid or methanol to form the 3-hydroxybutyrolactone.Preferably a strong acid is used for the acidification, such asphosphoric acid or hydrochloric acid. After adding water and extractingthe 3-hydroxybutyrolactone with a solvent such as ethyl acetate, the1,2,4-trihydroxybutane is left to the water layer.

It will be appreciated that the 3.4-hydroxybutyric acid methyl ester canbe converted to the acid or to a metal salt (preferably alkali metalsalt). There is no advantage to this step if the final product is the3-hydroxybutyrolactone.

Example 5 shows the preparation of (S)-4-hydroxymethyl gammabutyrolactone. The reaction Scheme III is as follows.

Various solvents can be used to extract the reaction products from thereaction mixture. The 3-hydroxybutane and 4-hydroxy methyl butyrolactoneare soluble in ethyl acetate. The 1,2,4-trihydroxybutane is soluble inwater. Other isolation techniques can be used. If the product is anintermediate to a further product the reaction mixture may be usedwithout isolating the product.

EXAMPLE 1

Direct Reduction of Malic Acid to Lactone (S)-Isomer

L-Malic acid (50 grams, 0.37 moles) was refluxed for 3 hours with 500 mlof anhydrous methanol containing 1% hydrogen chloride to form thedimethyl ester (Scheme II). The solution was concentrated to a syrup anddissolved in 200 ml of tetrahydrofuran. Anhydrous lithium chloride (32grams, 0.74 moles) was added followed by sodium borohydride (16 grams,0.42 moles) and methanol (80 ml) to provide the reducing agent. Themixture was stirred at room temperature (25° C.) for 6 hours, filtered,concentrated to dryness, treated with methanol (500 ml) containinghydrochloric acid (50 ml) and concentrated to dryness on a rotaryevaporator at a bath temperature of 35° C. A-further 500 ml of methanolwas added and the solution concentrated again. The process was repeatedtwice again and the final syrup partitioned between ethyl acetate andwater 20 ml: 400 ml. The ethyl acetate layer was recovered, dried andconcentrated to yield (S)-3-hydroxybutyrolactone (34 grams, 90%).

EXAMPLE 2

Direct Reduction of Malic Acid to Lactone (R)-Isomer

D-Malic acid (1 gram, 0.0075 moles) was refluxed for 3 hours with 10 mlof anhydrous methanol containing 1% hydrogen chloride to form thedimethyl ester (Scheme II). The solution was concentrated to a syrup anddissolved in 4 ml of tetrahydrofuran. Anhydrous lithium chloride (0.6grams. 0.014 moles) was added followed by sodium borohydride (0.32grams, 0.0084 moles) and methanol (2 ml) to provide the reducing agent.The mixture was stirred at room temperature(25° C.) for 6 hours,filtered, concentrated to dryness, treated with methanol (10 ml)containing hydrochloric acid (1 ml) and concentrated b dryness on arotary evaporator at a bath temperature of 35° C. A further 10 ml ofmethanol was added and the solution concentrated again. The process wasrepeated twice again and the final syrup partitioned between ethylacetate and water, 0.4 of: 8 ml. The ethyl acetate layer was recovered,dried and concentrated to yield (R)-3-hydroxybutyrolactone (0.6 grams,88%).

EXAMPLE 3

Direct Reduction of L-Malic Acid to (S)1,2,4-Trihydroxybutane

L-Malic acid (134 grams. 1 mole) was dissolved in methanol (1,200 ml)and concentrate hydrochloric acid (12 ml) was added The solution washeated under reflux in a 3 liter flask equipped with a calcium chloridedrying tube for 4 hours to provide the dimethyl ester (Scheme II) andthen concentrated to a syrup under vacuum (water aspirator). Moremethanol (200 ml) was added and the solution concentrated again toremove tracts of acid. The syrup was then dissolved in tetrahydrofuran(800 ml) and sodium borohydride (80 grams, 2.1 moles) and lithiumchloride (126 grams. 3 moles) added. The sodium borohydride was addedfirst carefully over a period of 10 minutes. There should be very littleeffervescence if all of the acid was removed earlier. The deals wascooled to 30° C. and the mixture was stirred for 15 minutes and thenmethanol (600 ml) was added over a period such that the temperature doesnot exceed 30° C. Concentrated (88%) phosphoric acid (1 mole) wascarefully added to destroy excess reagent (cooling if necessary). Themixture was then filtered through Whatman #1 paper and concentrated to asyrup to yield 130 grams of crude 1.2.4-trihydroxybutane.

EXAMPLE 4

Direct Reduction of L-Malic Acid to (S)-1,2.4-Trihydroxybutane

L-Malic acid (134 grams, 1 mole) was dissolved in methanol (1,200 ml)and concentrate hydrochloric acid (12 ml) was added The solution washeated under reflux in a 3 liter flask equipped with a calcium chloridedrying tube for 4 hours and then concentrated to a syrup under vacuum(water aspirator) to provide the dimethyl ester (Scheme II). Moremethanol (200 ml) was added and the solution concentrated again toremove trams of acid. The syrup was then dissolved in tetrahydrofuran(800 ml) and lithium chloride (126 grams, 3 moles) and sodiumborohydride (80 grams. 2.1 moles) added. The sodium borohydride wasadded carefully. There should be very little effervescence if all of theacid was removed earlier. The flask was fitted with a condenser anddrying robe and the mixture was stirred for 15 minutes and then methanol(600 ml) was added over a 5 minute period. The first 400 ml was added atonce and the remaining 200 ml was then added There is an increase intemperature of the mixture to 52°-54° C. resulting in a gentle refluxwith a steady release of hydrogen especially as the last 200 ml ofmethanol was added. The reaction mixture was tut cooled ova this period.The temperature drops back to room temperature after 1 hour and thereaction mixture wan then refluxed for 4 hours and cooled. It wasdiluted with 400 ml of methanol and concentrated HCl (200 ml) wascarefully added to destroy excess reagent (cooling if necessary). Themixture was then filtered through Whatman #1 paper, concentrated to asyrup and desalted through A cation exchange (DOWEX 50WX4-50, Made byDow Chemical Midland Mich.) and concentrated to a syrup which wasconcentrated 4 times from methanol (500 ml) an equal vol of water addedand extracted twice with 500 ml of ethyl acetate (to remove lactone ifthere is under-reduction) and the water fraction concentrated. Yields ofcrude product at end of ethyl acetate extract: 3-hydroxybutyrolactone,37 grams; 1,2,4-trihydroxybutane 126 grams.

EXAMPLE 5

Selective Reduction of (S)-4-Carboxy-γ-Butyrolactone to(S)4-Hydroxymethyl-γ-Butyrolactone. (Scheme III)

(S)-4-carboxy-γ-butyrolactone (130 grams, 1 mole) was dissolved inmethanol (1,200 ml) and concentrated hydrochloric acid (12-ml) wasadded. The solution was heated under reflux in a 3 liter flask equippedwith a calcium chloride drying tube for 4 hours to form the dimethylester (Scheme III). The mixture was then treated with calcium carbonate(20 grams) to remove acid and then concentrated to ˜300 ml under vacuum(water aspirator). The syrup was then dissolved in tetrahydrofuran (800ml) and sodium borohydride (20 grams, 1.05 moles) and lithium chloride(63 grams, 1.5 moles) added as the reducing agent. The sodiumborohydride was added first carefully over a period of 10 minutes. Verylittle effervescence was observed if all of the acid was removedearlier. The flask was cooled to 30° C. and the mixture stirred for 15minutes and then methanol (300 ml) was added over a period such that thetemperature does not exceed 30° C. Concentrated (88%) phosphoric acid (½mole) was carefully added to destroy excess reagent cooling ifnecessary). The mixture was then filtered through Whatman #1 paper andconcentrated to a syrup. The syrup was taken up in ethyl acetate andfiltered the filtrate concentrated and redissolved in water (400 ml).The solution was passed over a mixed bed ion exchange resin to removesalts. On concentration it yielded 100 grams (87%) of the desiredproduct

In a similar manner, other hydroxy alkyl substituted butyrolactones canbe prepared with 6 to 8 carbon atoms.

It is intended that the foregoing description be only illustrative ofthe present invention and that the present invention be limited only bythe hereinafter appended claims.

I claim:
 1. A process for producing a hydroxy substituted compound whichcomprises: reacting in a reaction mixture a 2-hydroxy substituted alkanediacid lower alkyl diester wherein the diacid contains 4 to 8 carbonatoms and alkyl contains 1 to 4 carbon atoms, with an alkali metalborohydride in a non-reactive solvent to produce the hydroxy substitutedcompound.
 2. A process for the preparation of a hydroxy substitutedgamma butyrolactone which comprises: reading in a reaction mixture a2-hydroxy substituted alkane diacid lower alkyl diester, wherein thediacid contains 4 in 5 carbon atoms and alkyl contains 1 to 4 carbonatoms, with an alkali metal borohydride in a non-reactive solvent at atemperature between about −10° and 60° C. to produce the hydroxysubstituted gamma butyrolactone and an alcohol as a by-product.
 3. Theprocess of claim 2 wherein the diester is4-carboxymethyl-4-hydroxybutyric acid-1-methyl ester and wherein thehydroxy substituted gamma butyrolactone is 4-hydroxymethylbutyrolactone.
 4. The process of any one of claims 2 or 3 wherein theester and the hydroxy substituted gamma butyrolactone are isomers. 5.The process of any me of claims 2 or 3 wherein one ester and the hydroxysubstituted gamma butyrolactone are isomers, and wherein the isomers are(S) isomers.
 6. The process is any one of claims 2 or 3 wherein theester and the hydroxy substituted gamma butyrolactone are isomers andwherein the isomer are (R) isomers.
 7. The process of any one of claims2 or 3 wherein as an additional step the reaction mixture is acidifiedand heated to volatilize the alcohol from the vendors mixture and thehydroxy substituted gamma, butyrolactone.
 8. The process of claim 2wherein the hydroxy substituted gamma butyrolactone is extracted fromthe reaction mixture with ethyl acetate.
 9. The process of claim 2wherein in the ester the lower alkyl is methyl, wherein the alkylenecontains five carbon atoms and wherein the butyrolactone is4-hydroxymethyl gamma butyrolactone.
 10. A process for the preparationof a compound selected from the group consisting of1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid -1-methyl ester andmixtures thereof which comprises: (a) reacting in a reaction mixturemalic acid with a molar excess of anhydrous methanol in the presence ofa catalytic mount of hydrogen ion end at a temperature between about 40°and reflux to produce hydroxybutane dioic acid di methyl ester; and (b)reducing the hydroxybutane dioic acid dimethyl ester with an alkalimetal borohydride to produce the compound.
 11. The process of claim 1027wherein about one equivalent of the alkali metal borohydride isreacted with the hydroxybutane dioic acid dimethyl ester andto producewherein the compound is substantially the 3.4-hydroxybutyric acid methylester.
 12. The process of claim 10 wherein about three equivalents ofthe alkali metal borohydride is reacted with the hydroxy butane dioicacid dimethyl ester and the compound is substantially the1,2,4-trihydroxybutane.
 13. The process of any one of claims 10, 11 or12 wherein the malic acid is an isomer.
 14. The process of any one ofclaims 11 or 12 wherein the malic acid is an isomer and the humid is the(S) isomer.
 15. The process of any one of claim 11 or 12 wherein themalic acid is an isomer and the isomer is the (R) isomer.
 16. Theprocess of claim 10 wherein the 3.4-dihydroxybutyric acid methyl esteris extracted from the reaction mixture with ethylacetate.
 17. Theprocess of claim 10 wherein the reaction mixture in step (a) isrefluxed.
 18. The process of claim 11 wherein as an additional step the3,4-dihydroxy butyric acid -1-methyl ester is acidified and heated tovolatilize the methanol from the reaction mixture from step (a) and toproduce the hydroxylactone 4-hydroxymethyl butyrolactone.
 19. Theprocess of claim 18 wherein about one equivalent of the alkali metalborohydride which is lithium borohydride is reacted with the hydroxybutane dioic acid dimethyl ester to produce the 3,4-dihydroxybutyricacid -1-methyl ester.
 20. The process of claim 10 wherein the1,2,4-trihydroxybutane is extracted from the reaction mixture usingwater.
 21. The process of claim 19 wherein the malic acid is as the (R)isomer and the compound 3,4 dihydroxybutyric acid- 1 -methyl esterproduced is the (R) isomer.
 22. The process of claim 19 wherein themalic acid is as the (S) isomer and the compound 3,4-dihydroxy butyricacid- 1 -methyl ester produced is the (S) isomer.
 23. The process ofclaim 10 wherein in addition the 3,4-hydroxy butyric acid -1-methylester is separated and reacted with an acid to form 3-hydroxy gammabutyrolactone.
 24. The process of claim 1 wherein the alkali metalborohydride is lithium borohydride.
 25. The process of claim 2 whereinthe alkali metal borohydride is lithium borohydride.
 26. The process ofclaim 10 wherein the alkali metal borohydride is lithium borohydride.27. A process for the preparation of 3,4-dihydroxybutyric acid- 1-methyl ester which comprises: (a) reacting in a reaction mixture malicacid with a molar excess of anhydrous methanol in the presence of acatalytic amount of hydrogen ion and at a temperature between about 40°and reflux to produce hydroxybutane dioic acid dimethyl ester; and (b)reducing the hydroxybutane dioic acid dimethyl ester with an alkalimetal borohydride to produce the 3,4 -dihydroxybutyric acid- 1 -methylester.
 28. The process of any one of claims 11 or 27 wherein the malicacid is an isomer.
 29. The process of claim 11 wherein the malic acid isan isomer and the isomer is the (S) isomer.
 30. The process of claim 11wherein the malic acid is an isomer and the isomer is the (R) isomer.31. The process of claim 27 wherein the 3,4-dihydroxybutyric acid methylester is extracted from the reaction mixture with ethylacetate.
 32. Theprocess of claim 27 wherein the reaction mixture in step (a) isrefluxed.
 33. The process of claim 27 wherein in addition the3,4-hydroxy butyric acid- 1 -methyl ester is separated and reacted withan acid to form 3 -hydioxy gamma butyrolactone.
 34. The process of claim27 wherein the alkali metal borohydride is lithium borohydride.